6alpha, 9alpha, 11beta-trichloro and 6alpha-fluoro-9alpha, 11beta-dichloro pregnenes



United States Patent DIiZHLQRO PREGNENES Albert Bowers, Mexico City, Mexico, assignor, by mesne assignments, to Syntex Corporation, a corporation of Panama No Drawing. Filed Feb. 18, 1960, Ser. No. 9,435 Claims priority, application Mexico, Feb. 18, 1959,

53,717; Oct. 20, 1959, 56,285 22 Claims. (Cl. 260-43955) The present invention relates to novel cyclopentanophenanthrene derivatives and to a novel process for the preparation thereof. 1

More particularly the invention relates to novel 6ot,9oc,11/3-U1Cl1l010 and 6oc-fll10r0 9oc,11,B-diChl0r0-A pregnenes and A -pregnadienes of the following formula:

CHzOR In the above formula R represents hydrogen or a hydrocarbon carboxylic acyl group containing from 1 to 12 carbon atoms; R represents hydroxy or an acyloxy group derived from a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms; R represents hydrogen, a-methyl, B-methyl, a-hydroxy or a-acyloxy wherein the acyl group is derived from a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms; and R and R jointly may represent the grouping atoms or aromatic groups containing from 6 to 12 carbon atoms. Such ketals or acetals are formed by the reaction of the 16a,17u-dihydroxy compound with an aldehyde or ketonesuch as acetone, methylethylketone, butanone,

,cyclohexanone, formaldehyde, acetaldehyde and furfural.

X represents chlorine or fluorine.

The acyl groups are derived from hydrocarbon carboxylic acids containing from 1 to 12 carbon atoms and may be saturated or unsaturated, straight chain or branched chain aliphatic, cyclic, cyclic-aliphatic, aromatic and may be substituted by hydroxy, an acyl-oxy group containing from 1 to 12 carbon atoms, an alkoxy group containing from 1 to carbon atomsor by halogen such as fluorine, chlorine or bromine. Typical ester groups are the acetate, propionate, butyrate, hemisuccinate, enanthate, caproate, benzoate, trimethylacetate, phenoxyacetate, phenylpropionate and fl-chloropropionate.

The novel compounds of the present invention are .valuable steroids having pronounced anti-inflamatory,

glucocorticoid and anti-estrogenic activity. The novel trihalo compounds are of particular value since they can be administered topically without producing systemic eliects when used for the alleviation of inflammatory conditions.

'in which R represents hydrogen or hydrocarbon. groups such as aliphatic radicals containing from 1 to 8 carbon The preparation of the novel compounds which form 3,2hlfi9l Patented Aug. 17, 19 65 the subject matter of the present invention may be illustrated by the following equation:

CHzOR OHgOR 0.0g or In the above equation, R, R, R and X represent the same groups as heretofore set forth.

In practicing the process above outlined the 11 pregnadiene-3,20-dione compounds are treated with 1 molar equivalent of chlorine in an inert solvent such as carbon tetrachloride or methylene chloride to produce the corresponding 9a,11fi dichloro-M-pregnene 3,20-dione pounds by treatment of the latter with an organic sulfonyl chloride and more particularly methanesulfonyl chloride in a solvent such as dimethylformamide in the presence of a tertiary amine such as pyridine.

The ester groups at C-21 and C-16 are formed in the conventional manner by treating a pyridine solution of the steroid with the respective acid anhydride or chloride; the hydroxyl group at C-17 is esterified by reaction with acetic anhydride and acetic acid in the presence of p-toluenesulfonic acid when the acetate is desired or with other ,acid anhydrides in benzene solution in the presence of p-toluenesulfonic acid. If the free compounds are de sired, the ester groups are hydrolyzed by alkaline treatment as for example with dilute methanolic potassium hydroxide solution at low temperature and under an atmosphere of nitrogen.

Similarly, potent progestational agents such as ,11B- dichloro progesterone, 90:,1IB-dichloro-l9-nor-progester one, 901,1 IB-dichloro-17e-hydroxy-progesterone, 901,1 1.6-

'dichloro-171x-acyloxy-progesterone, particularly the acetoxy, propionoxy, and the A derivatives of all the foregoing, can be prepared in the same manner from the corresponding A -pregnadiene 3,20 dione; 19'-nor- 'A -pregnadiene-3,20-dione and from 17a-hydroxy and Hts-hydrocarbon carboxylic acyloxy-A -pregnadiene- "3,20-dione which in turn are prepared from the corresponding A -pregnene-1l-hydroxy compounds in the manner set forth above.

9 The following preparations and examples serve to illustrate but are not intended to limit the present invention:

PREPARATION 1 A mixture of 4 g. of 6a-fiuoro-hydrocortisone-acetate, 2 g. of methanesulfonyl chloride, 60 cc. of dimethylformamide and 4 cc. of pyridine was heated at 80 C. for one hour, cooled, diluted with water and the product was extracted with ethyl acetate; the extract was washed with water, dried over anhydrous sodium sulfate and the ethyl acetate was evaporated. By recrystallization of the residue from acetone-hexane there was obtained 6a-fiuoro- A -pregnadiene-17a,21-diol-3,20-dione 21-acetate.

PREPARATION 2 By following the method described in Preparation 1, 16a-methyl-6a-fiuoro-hydrocortisone 21-acetate described in copending application Serial No. 789,242, filed on January 27, 1959, and 16fi-methyl-6a-fiuoro-hydrocorti- :sone 21-acetate described in copending application Serial No. 792,962, filed on February 13, 1959, now abandoned, were converted into the corresponding 16u-methyl-6afiuoro-A -pregnadiene-l7e,21-diol-3,20-dione 21-acetate and 16fl-methyl-6a-fiuoro-A -pregnadiene-17a,21- diol3,20-dione.

PREPARATION 3 By following the method described in Preparation 1, 6a-chloro-16a-hydroxy-hydrocortisone 160:,21 diacetate described in copending application Serial No. 753,626 filed on August 7, 1958, now U.S. Patent No. 2,997,489, issued August 22, 1961, and the 16oa17a-acetonide of 6achloro-16ahydroxy-hydrocortisone 21-acetate described in copending application Serial No. 819,545, filed June 11, 1959, now US. Patent No. 3,126,375, issued March 24, 1964, were converted into the corresponding 60:- chloro-A -pregnadiene-16a,17oc,21 triol 3,20-dione- 16e,21-diacetate and the 16a,17e-acetonide of 6a-ClJlOI'O- M -pregnadiene-16a,17a,2l-triol-3,20-dione 21 acetate.

PREPARATION 4 By following the method described in Preparation 1, there Were obtained a-chloro-lG/B-methyI-M- -pregnadiene-l7a,21diol-3,20-dione 2l-acetate and 601-011101- 1Gu-methyl-A -pregnadiene-l7a,21-diol,3,20-dione 21- acetate from the corresponding 6e-chloro-16/3-metl1ylhydrocortisone 2l-acetate described in copending application Serial No. 824,200, filed July 1, 1959, now abandoned, and from the 6oc-Clll0f0-1Got-IIIClLhYl-hYdi'OCOItlSOHG 2l-acetate described in copending application Serial No. 825,655, filed on July 8, 1959, now abandoned.

PREPARATION 5 By following the method of Preparation 1, 6u-chl0r0- hydrocortisone-2l-acetate described by Ringold et al. in J. Am. Chem. Soc., volume 80, pages 64646465, December 5, 1958, was converted into 6a-chloro-A -preg nadienc-17a,21-diol-3,20-dione-21-acetate.

PREPARATION 6 To 1.0 g. of 6-a-fiuoro-16a-hydroxy-hydrocortisone 21- acetate, described by Mills et al. in J. Am. Chem. Soc., volume 81, pages 1264-1265, March 5, 1959, there was added 1 cc. of propionic anhydride in ml. of dry pyridine. The reaction mixture was left at room temperature overnight and was then poured with stirring into ice water. The resulting precipitate was filtered, washed with water and crystallized from acetone-hexane to give 6tx-fluoro-16u-hydroxy-hydrocortisonel 6a-propionate 21- acetate. By following the method of Preparation 1, the latter compound was converted into 6a-fiLl01O-A pregnadiene-16a,17a,21-triol-3,20-dione 16a propionate 21-acetate.

recrystallized from acetone-hexane.

4 PREPARATION 7 A solution of 1.6 g. of 6a-fiuoro-A -pregnadiene- 17a,21-diol-3,20-di0ne 21-acetate in 4 cc. of chloroform was treated under continuous stirring and in the course of 5 minutes with a solution of 324 mg. of chlorine in 10 cc. of carbon tetrachloride. The mixture was kept for 2 minutes at room temperature, then treated with 10 cc.

of 5% aqueous sodium carbonate solution and the product was extracted several times with chloroform. The combined extract was washed with Water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness. The residue crystallized from acetone-hexane to yield 60:- iiuoro-9a,11fl-dichloro-A4-pregnene 17oc,21 diol 3,20- dione 21-acetate.

A solution of 500 mg. of the above compound in 24 cc. of t-butanol containing 0.08 cc. of pyridine was treated with 270 mg. of recently sublimed selenium dioxide and the mixture was refluxed with continuous stirring for 48 hours under an atmosphere of nitrogen. The solution was filtered through celite, the solvent was removed under reduced pressure and the residue was chromatographed on neutral alumina. There was thus obtained 6a-fluoro- 9a,1l,B-dichloro-A -pregnadiene 17a,2l-diol-3,20-dione 21-acetatc.

A mixture of 1 g. of the above compound and 50 cc. of 1% methanolic potassium hydroxide solution was kept at a temperature around 0 C. for 1 hour under an atmosphere of nitrogen, acidified with acetic acid, concentrated to a small volume and diluted with water; the precipitate formed was collected by filtration, washed with Water, dried and recrystallized from acetone-hexane, thus yielding the free 6 xfluoro-9a,1lfi-dichloro-n -pregnadiene-17a,21-diol-3,20-dione.

A mixture of 500 mg. of the above compound, 5 cc. of pyridine and 1 cc. of propionic anhydride was kept overnight at room temperature, poured into water, heated on the steam bath for half an hour, cooled and the precipitate was collected, washed with water, dried and recrystallized from acetone-hexane, thus furnishing 6afluoro 9a,11B-dichloro-A -pregnadiene-17a,21-diol-3,20 dione 21-propionate.

A mixture of 300 mg. of the above compound, 15 cc. of glacial acetic acid, 3 cc. of acetic anhydride and 300 mg. of p-toluenesulfonic acid was kept overnight at room temperature and then poured into water; the mixture was heated on the steam bath for half an hour, cooled and the precipitate wa collected, washed with water, dried and There was thus obtained 6a-fluoro-9a,11fl-dichloro-A -pregnadiene-17a,21- diol-3,20-dione 17-acetate-2l-propionate.

Example 11 A solution of 1 g. of 6u-fiuO1'O-9a,11B-diChl0rO-A 'pregnene-17a,21-diol-3,20-dione 2l-acetate of the previous example, in 50 cc. of benzene was mixed with 3 g. of caproic anhydride and 1 g. of p-toluenesulfonic acid and kept at room temperature for 72 hours. The mixture was then consecutively washed with water, 5% sodium carbonate solution and again with water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness. By chromatography of the residue on neutral pregnene-17a,21-diol-3,20-dione 17-caproate-21-acetate.

Example III By essentially following the procedure described in Example I, 5 g. of 6a-fluoro-16a-methyl-A -pregnadienel7 a,2l.-diol-3,20-dione 21-acetate was converted into 6afiuoro 1600 methyl-901,1lfi-dichloroM-pregnene-170,21- dio1-3,20-dione 21-acetate and then into 6cc-fiI1OIO-16cc- .methyl 90:,110- dichloro A -pregnadiene-17a,21-diol 3,20-dione 21-aeetate.

Example IV By essentially following the procedure described in Example I, 5 g. of Goa-chloro-A -pregnadiene-160c,170r,21-

.triol-3,20-dione 16,21-diacetate was converted into 601,9,

11fl-trichloro-A -pregnene-16a,170r,21-triol-3,20-dione 16, ZI-diacetate and then into 60,90r,11B-t1ichloro-A -pregna dione-160i,1700,2l-triol-3,20-dione 16,2l-diacetate; by the hydrolysis with methanolic potassium hydroxide there was obtained the free 60,900,11fl-trichloro-A -pregnadiene l600,170c,21-trio'l-3,20-dione.

A mixture of 2 g. of the latter compound, 50 cc. of acetone and 1 cc. of 70% perchloric acid was kept at room temperature'for 1 hour, neutralized with sodium bicarbonate solution and diluted with saturated aqueous pyridine solution there was obtained the 16,17-acetonide of 600,9rx,1 l,B-trichloro-A -pregnadiene-1 6a,170,2l-triol-3, ZO-dione ZI-acetate. A

Example V A mixture of 1 g. of 60,90r,1lp-trichloro-A -pregnene- 160;,17a,21-triol-3,20-dione 16,2l-diacetate, intermediate in the previous example, and 50 cc. of a 1% solution of potassium hydroxide in methanol was kept at 0 C., under the conditions described for this hydrolysis in Example I; there wasithus obtained the free 6a,90r,l1fl-trichloro-A -pregnenel 600, 17cc,21-TIlOl-3 ,ZO-dione.

A solution of 500 mg. of the above compound in 50 cc. of chloroform was treated with 2 g. of paraldehyde and a few drops of 3 N perchloric acid and stirred at room temperature for 2 hours. After diluting with water the chloroform layer was separated, washed with aqueous saturated bicarbonatesolution and then with water, the chloroform was distilled and the residue was purified by chromatography on neutral alumina, thus yielding the 16, 17-acetaldehyde-acetal of 600,900,1lfi-trichloro-A -pregnene 16rx,170r,21-triol-3,20-dione. Upon subsequent treatment with propionic anhydride in pyridine solution (cf. of Example I) there was obtained the 2l-propionate if the latter compound.

Example VI By applying the method of Example I, to the 16,17-

acetonide of r-chloro-A -pregnadiene-l60,170t-21-- triol-3,20-dione Zl-acetate there was obtained in the step of chlorination the 16,17-acetonide of 60,90r,11/3-trichloro- N -pregnene-l6a,170r,21-triol-3,20-dione 2lacetate, which upon subsequent dehydrogenation with selenium dioxide afforded the 16,17-acetonide of 600,90r,11,6-trichl-oro-A pregnadiene-l60r,l70r,21-triol3,20*dione Zl-acetate, identi cal with the final compound of Example IV.

Example VII By essentially following the method described in Example IV, 60r-fiuoro-A -pregnadiene-l60r,170t,21-triol of Example VIII.

pion'ate ZI-acetate.

.3,20-dione-16,21-diacetate was converted into 6oc-fll10l0- 911,115 dichloro-A -pregnene-lou,17u,21-triol-3,20-dione- A pregnadiene 1600,170:,21-triol-3,20-dione-l6,2l-diacetate; by hydrolysis with methanolic potassium hydroxide there wa obtained the free 6otfl110IO-90c,11fi-dl6hl010- A -pregnadiene-16a,17a,2l-triol-3,20-dione.

"By treatment with acetone in the presence of perchloric acid as set forth in Example IV, the 1-6 l7-acetonide of 6ocfiuoro :,115 dichloro A pregnadiene 1600, 170r,12l-t-riol-3,20-dione was formed, which upon subsequent treatment with acetic anhydride in pyridine solution was transformed into the 16,17-acetonide of 60z-fluoro 911,115 dichloro A pregnadiene 16a,1'7a,Z1- triol-3,20-dione ZI-acetate.

Example IX The 16,2l-diacet-ate of 60c-fi11OI0-9og11B-dlChl0rO-A pregnene l6oc,l7u,21 triol 3 ,20 dione described in Example VIII was hydrolyzed in the manner set forth in Example V to produce the free 6a-fiuoro-90alll8-dichloro A pregnene 1600,1700,21 triol 3,20-dione and then subsequently treated with paraldehyde as described in the aforementioned Example V to produce the 16,17- acetaldehyde acct-a l of 60r-fluoro-90c,1lfi-dichloro-N-pregnene 1611,1711 21 triol 3,20 dione.

Example X By applying the method of Example I to the 16,17- acetonide of 600-fluoro M1901) pregnadiene-1600,l700,21- triol-3,20-dione ZI-acetate, there was obtained the 16,17- acetonide of 60c-flllOI0-9oc,1l'B-dlChlOlO- -p-regnene-ir, 1701,21 triol 3,20 dione ZI-acetate. Dehydrogenation with selenium dioxide under the conditions described in Example I afi orded the 16,17-acetonide of 60r-fluoro 90,11/3 dichloro A pregnadiene 1604,1711, 21 triol- 3,20-dione 21-"lcetate, identical with the final compound Eadam ple XI 7 By following the methods of Example I, 600-ch-loro- A pregnadiene 1706,21 diol 3,20 dione 21 acetate was converted into 600,90,1l'fi-trichloro-A -pregnene- 17a,21-diol-3,'20-di0ne ZI-acetate and then into 6oc,90z,11fitrichloro A pregnadiene 1711,21 diol 3,20 dione ZI-acetate.

Example XII 'a'cetate described in thelpreceding example was treated with propionic anhydride to produce -60r,90r,l:1;3-trioh'loro- A pregnene 1706,21 diol 3,20 dione r-pro- Example XIII By following the method of Example I, 6u-chloro- 1600 methyl A pregnatliene 170,2l diol- 3,20-

dione 2l-acetate and the corresponding loflnrrethyl de- 'rivative were converted into 600,90r,-11,B-trichloro-160r-methyl A pregnene 170r,2l diol 3,20 dione 21acetate and 601,900,111? trichloro 16B methyl A pre'gnenel7u,2l-diol-3,20-dion=e Ql-acetate; Upon subsequent dehydrogenation with selenium dioxide the corresponding 601,900,1 1 trichlolo 1600 methyl A pnegnadiene- 1704,21 diol 3,20 dione ZI-aoetate and 601,901,115-

tri'chloro 16B methyl A pregnadiene 1704,21-

'diol-3,20-dione ll-acetate were obtained.

By following the saponification method with 1% methanolic potassium hydroxide solution, described in Excap Di wherein X is selected from the group consisting of fluorine and chlorine; Z is selected from the group consisting of a double bond between C1 and C-2 and a saturated linkage between 0- 1 and CQ; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 canbon atoms; R is selected from the group consisting of hydroxy and a hydrocarbon oarboxylic acyloxy group containing less than 12 carbon atoms; R is selected from the group conin which R is selected from the grouping consisting of hydrogen, lower alkyl and aryl containing from 6 to 12 carbon atoms.

2. 6a,9a,11/3 trichloro A pregnadiene-16a,17a,21- triol-3,20-dione.

3. 6a-iiluoro-9a,1lfl-dichloro A -pregnene-17a,21,diol- 3, 20-dione .diol-3,20-dione.

5. 6u-fiuoro-9a,11,B-dichloro A -pregnadiene-16a,17a, 21-thiol-3,2-0-dione. v

7. The 1'6,1 7-acetonide of 601,904,11 fl-trichloro-o -pregnadiene-l-6u,l7a,2l-triol-3,20-dione.

'8, The 16,17-acetonide of 6ix-fluoro-9a,llp-dichloro- A -pregnadiene- 160:,17a,21-triol-3,20-dione-21-acetate 10. The hydrocarbon carboxylic acid esters of less than 12 carbon atoms of 6a-fluoro-9a,1-1fi-dichloro-1'6-methy1- A -pregnene-17u,21-diol-3,20-dione.

8 11. The hydrocarbon carboxylic acid esters of less than 12 carbon atoms of '6a-fiuoro-9a,llfi-dichloro-lo-methyl- A -pregnadiene-17a,21-diol-3,20-dione.

12. 6oc-fiuOIO-9oc, l1 fl-dichloro-l6a-methyl A f-pregnadiene-l7a;21-diol-3,20-dione-2l-acetate.

1'3. The hydrocarbon carboxylic acid esters of less than 12 carbon atoms of 6a-iluoro-9a,l l B-dichloroA -pregnadiene l7a,21-diol-3,20-dione.

14. The hydrocarbon carboxylic acid esters of less than 12 carbon atoms of 6a-fiuoro-9a,11;3-dich1oro-A -pregnadiene-16a,17a,2l-triol-3,20-dione.

15. 6oc-fluOr0-9a,1lfi-diChlOIO A pregnadiene 160., 17a,21-triol-3,20-dione-16,21-diacetate.

15. 6a-fluoro-9a,11B-dichloro A -pregrradiene-17a,21- diol-3,Q0-dione 2l-acetate.

17. The hydrocarbon carboxylic acid esters of less than 12 carbon atoms of 6a,9a,11B-trichloro-A -pregnadiene- 17u,21-diol-3,2()-dione.

18. The hydrocarbon carboxylic acid esters of less than 12 carbon atoms of 6a,9a,11B-trichlor0-A -pregnadiene- 16a,1701.21-triol-3,20-dione.

19. The hydrocarbon carboxylic acid esters of less than 12 carbon atoms of 6a,9oc,1lB-trichloro-l6-methyl-A pregnadiene-17a,21-dio'l-3,20-dione.

2%. The hydrocarbon carboxylic acid esters of less than 12 carbon atoms of the 16,17-acetonide of 6lX-fiUOl'O-9t1, 11/3 dichloro A pregnadiene 16u,17a,21-trio1-3,20-

'dione.

21. A compound formula:

CHzORl l... Cl 3- 1: all

wherein R is selected from the group consisting of hydrogen and methyl and R is selected from the group consisting of hydrogen and lower alkanoyl.

22. A compound of the following formula:

ca ed C:O

2,894,963 7/59 Gould et .al. 260397.45 2,916,486 12/59 Babcock et a1. 260239.55

OTHER REFERENCES Ringold et al.: J. A. C. 8., vol. 80, 1958, p. 6464.

LEWIS GOTTS, Primary Examiner.

L. H. GASTON, MORRIS LIEBMAN, Examiners. 

1. A COMPOUND OF THE FOLLOWING FORMULA:
 7. THE 16,17-ACETONIDE OF 6A,9A,11B-TRICHLORO-$1,4-PREGNADIENE-16A,17A,21-TRIOL-3,20-DIONE. 